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mTOR

The mammalian target of rapamycin (mTOR; EC 2.7.11.1), a phosphoinositide 3-kinase-related protein kinase, controls cell growth in response to energy, nutrients, growth factors and other environmental cues, and it figures prominently in cancer. It belongs to the phosphoinositide 3-kinase (PI3K)-related protein kinase (PIKK) family. mTOR assembles into two complexes with distinct inputs and downstream effects. mTOR complex 1 (mTORC1) is defined by its RAPTOR subunit which is replaced by RICTOR in mTOR complex (mTORC2).mTORC1 regulates cell growth by promoting translation, ribosome biogenesis and autophagy. Its activation requires nutrients and amino acids, which result in the RAPTOR-mediated recruitment of mTORC1 to lysosomes and late endosomes, and co-localization with its activator, the small GTPase RHEB. mTORC1 substrates include the eIF4E-binding protein 1 (4E-BP1) and ribosomal S6 kinases (S6K).mTORC2 responds primarily to growth factors, promoting cell-cycle entry, cell survival, actin cytoskeleton polarization and anabolic output. Its substrates include the Ser/Thr protein kinases Akt, SGK and PKC, which share the hydrophobic motif phosphorylation site with S6K1.Noteworthy, rapamycin, which forms a ternary complex with the FK506-binding protein 12 (FKBP12) and the FRB domain of mTOR, is thought to be an allosteric inhibitor. Rapamycin–FKBP12 inhibits mTORC1 to a variable extent that is substrate and phosphorylation-site dependent, while it does not bind to mTORC2[1],[2].Axon Ligands™ that block mTOR activity are also listed in the section for PI3K/AKT/mTOR signaling.